The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. While current exposure levels to environmental agents does not represent an acute injury, disruption to the nervous system may be associated with either a structural alteration in the formation of the neural network and/or in nervous system functioning. The formation and interactions between the various cell types in the brain are critically timed events.Such windows of vulnerability is assummed to be a major component in the differential susceptibility of the developing organism to environmental insult. This project examines chemical induced perturbations during development of the nervous system as indicated by various alterations in the morphology and molecular profile in the developing brain and assoicated neurobehavioral outcome of such exposure. Using these approaches we have examined alterations in the murine model of low-level lead neurotoxicity. Limited data currently exists with regards to developmental neurotoxicology in the mouse thus, limiting the ability to utilize the power of genetics that this species offers. Our current studies have identified critical windows of post-natal development susceptible to lead neurotoxicity and have identified distinct structural and behavioral alterations(3). This data is now being used to establish protocols to examine the impact of the underlying genetic background on the manifestation of developmental neurotoxicity. Additional studies examining the long term effect of early developmental lead exposure in the non-human primate have demonstrated a possible link with the increase in amyloid plaque formation with aging. We have identified structural alterations in neuronal dendritic aborization that may help to explain the various and diverse effects as a result of exposure to PCBs (5). In examining a possible increased vulnerability of the developing brain as a function of an altered immune system, we have conducted an extensive study to replicate and expand previous work suggesting a differential effect of ethyl mercury (administered as thimerosal) in the immunologically altered SJL mice. Working with the Toxicology Operations Branch, we have establishing a testing protocol to examine the neurodevelopmental toxicities of environmental chemicals that perturb thyroid hormone homeostatic maintenance during gestational and postnatal development. In addition to changes occurring during development, this project will also focus on questions related to either latent effects or effects on the aged brain as the result of early developmental exposure to environmental chemicals. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, molecular techniques to examine mRNA levels, as well as assessment of neurobehavioral functioning.